Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T69563 | Target Info | |||
| Target Name | Oxalosuccinate decarboxylase (IDH1) | ||||
| Synonyms | PICD; NADP(+)-specific ICDH; Isocitrate dehydrogenase [NADP] cytoplasmic; IDP; IDH; Cytosolic NADP-isocitrate dehydrogenase | ||||
| Target Type | Successful Target | ||||
| Gene Name | IDH1 | ||||
| Biochemical Class | Short-chain dehydrogenases reductase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Alpha-ketoglutaric acid | Ligand Info | |||
| Canonical SMILES | C(CC(=O)O)C(=O)C(=O)O | ||||
| InChI | 1S/C5H6O5/c6-3(5(9)10)1-2-4(7)8/h1-2H2,(H,7,8)(H,9,10) | ||||
| InChIKey | KPGXRSRHYNQIFN-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 51 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 7PJM Crystal Structure of Ivosidenib-resistant IDH1 variant R132C S280F in complex with NADPH and Ca2+/2-Oxoglutarate | ||||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | Yes | [1] |
| PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGC132 HAYGDQYRAT142 DFVVPGPGKV152 EITYTPSDGT 162 QKVTYLVHNF172 EEGGGVAMGM182 YNQDKSIEDF192 AHSSFQMALS202 KGWPLYLSTK 212 NTILKKYDGR222 FKDIFQEIYD232 KQYKSQFEAQ242 KIWYEHRLID252 DMVAQAMKSE 262 GGFIWACKNY272 DGDVQSDFVA282 QGYGSLGMMT292 SVLVCPDGKT302 VEAEAAHGTV 312 TRHYRMYQKG322 QETSTNPIAS332 IFAWTRGLAH342 RAKLDNNKEL352 AFFANALEEV 362 SIETIEAGFM372 TKDLAACIKG382 LPNVQRSDYL392 NTFEFMDKLG402 ENLKIKLAQA 412 KLLEH
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| PDB ID: 4L03 Crystal Structure Analysis of human IDH1 mutants in complex with NADP+ and Ca2+/alpha-Ketoglutarate | ||||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [2] |
| PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNDTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGR132 HAYGDQYRAT142 DFVVPGPGKV152 EITYTPSDGT 162 QKVTYLVHNF172 EEGGGVAMGM182 YNQDKSIEDF192 AHSSFQMALS202 KGWPLYLSTK 212 NTILKKYDGR222 FKDIFQEIYD232 KQYKSQFEAQ242 KIWYEHRLID252 DMVAQAMKSE 262 GGFIWACKNY272 DGDVQSDSVA282 QGYGSLGMMT292 SVLVCPDGKT302 VEAEAAHGTV 312 TRHYRMYQKG322 QETSTNPIAS332 IFAWTRGLAH342 RAKLDNNKEL352 AFFANALEEV 362 SIETIEAGFM372 TKDLAACIKG382 LPNVQRSDYL392 NTFEFMDKLG402 ENLKIKLAQA 412 KLSLEH
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| PDB ID: 3INM Crystal structure of human cytosolic NADP(+)-dependent isocitrate dehydrogenase R132H mutant in complex with NADPH, ALPHA-KETOGLUTARATE and CALCIUM(2+) | ||||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | Yes | [3] |
| PDB Sequence |
KISGGSVVEM
13 QGDEMTRIIW23 ELIKEKLIFP33 YVELDLHSYD43 LGIENRDATN53 DQVTKDAAEA 63 IKKHNVGVKC73 ATITPDEKRV83 EEFKLKQMWK93 SPNGTIRNIL103 GGTVFREAII 113 CKNIPRLVSG123 WVKPIIIGHH133 AYGDQYRATD143 FVVPGPGKVE153 ITYTPSDGTQ 163 KVTYLVHNFE173 EGGGVAMGMY183 NQDKSIEDFA193 HSSFQMALSK203 GWPLYLSTKN 213 TILKKYDGRF223 KDIFQEIYDK233 QYKSQFEAQK243 IWYEHRLIDD253 MVAQAMKSEG 263 GFIWACKNYD273 GDVQSDSVAQ283 GYGSLGMMTS293 VLVCPDGKTV303 EAEAAHGTVT 313 RHYRMYQKGQ323 ETSTNPIASI333 FAWTRGLAHR343 AKLDNNKELA353 FFANALEEVS 363 IETIEAGFMT373 KDLAACIKGL383 PNVQRSDYLN393 TFEFMDKLGE403 NLKIKLA |
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| PDB ID: 4KZO Crystal Structure Analysis of human IDH1 mutants in complex with NADP+ and Ca2+/alpha-Ketoglutarate | ||||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [2] |
| PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 HAYGDQYRAT142 DFVVPGPGKV152 EITYTPSDGT 162 QKVTYLVHNF172 EEGGGVAMGM182 YNQDKSIEDF192 AHSSFQMALS202 KGWPLYLSTK 212 NTILKKYDGR222 FKDIFQEIYD232 KQYKSQFEAQ242 KIWYEHRLID252 DMVAQAMKSE 262 GGFIWACKNY272 DGDVQSDSVA282 QGYGSLGMMT292 SVLVCPDGKT302 VEAEAAHGTV 312 TRHYRMYQKG322 QETSTNPIAS332 IFAWTRGLAH342 RAKLDNNKEL352 AFFANALEEV 362 SIETIEAGFM372 TKDLAACIKG382 LPNVQRSDYL392 NTFEFMDKLG402 ENLKIKLAQA 412 KLSL
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .AKG or .AKG2 or .AKG3 or :3AKG;style chemicals stick;color identity;select .A:77 or .A:94 or .A:96 or .A:97 or .A:100 or .A:109 or .A:139 or .A:275 or .A:278 or .A:279 or .A:306 or .A:308; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 4L06 Crystal Structure Analysis of human IDH1 mutants in complex with NADP+ and Ca2+/alpha-Ketoglutarate | ||||||
| Method | X-ray diffraction | Resolution | 2.28 Å | Mutation | Yes | [2] |
| PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGR132 HAYGDQDRAT142 DFVVPGPGKV152 EITYTPSDGT 162 QKVTYLVHNF172 EEGGGVAMGM182 YNQDKSIEDF192 AHSSFQMALS202 KGWPLYLSTK 212 NTILKKYDGR222 FKDIFQEIYD232 KQYKSQFEAQ242 KIWYEHRLID252 DMVAQAMKSE 262 GGFIWACKNY272 DGDVQSDSVA282 QGYGSLGMMT292 SVLVCPDGKT302 VEAEAAHGTV 312 TRHYRMYQKG322 QETSTNPIAS332 IFAWTRGLAH342 RAKLDNNKEL352 AFFANALEEV 362 SIETIEAGFM372 TKDLAACIKG382 LPNVQRSDYL392 NTFEFMDKLG402 ENLKIKLAQA 412 KLS
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .AKG or .AKG2 or .AKG3 or :3AKG;style chemicals stick;color identity;select .A:77 or .A:94 or .A:96 or .A:97 or .A:100 or .A:109 or .A:132 or .A:275 or .A:279 or .A:306 or .A:308; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 4L04 Crystal Structure Analysis of human IDH1 mutants in complex with NADP+ and Ca2+/alpha-Ketoglutarate | ||||||
| Method | X-ray diffraction | Resolution | 2.87 Å | Mutation | No | [2] |
| PDB Sequence |
ISGGSVVEMQ
14 GDEMTRIIWE24 LIKEKLIFPY34 VELDLHSYDL44 GIENRDATND54 QVTKDAAEAI 64 KKHNVGVKCA74 TITPDEKRVE84 EFKLKQMWKS94 PNNTIRNILG104 GTVFREAIIC 114 KNIPRLVSGW124 VKPIIIGRHA134 YGDQYRATDF144 VVPGPGKVEI154 TYTPSDGTQK 164 VTYLVHNFEE174 GGGVAMGMYN184 QDKSIEDFAH194 SSFQMALSKG204 WPLYLSTKNT 214 ILKKYDGRFK224 DIFQEIYDKQ234 YKSQFEAQKI244 WYEHRLIDDM254 VAQAMKSEGG 264 FIWACKNYDG274 DVQSDSVAQG284 YGSLGMMTSV294 LVCPDGKTVE304 AEAAHGTVTR 314 HYRMYQKGQE324 TSTNPIASIF334 AWTRGLAHRA344 KLDNNKELAF354 FANALEEVSI 364 ETIEAGFMTK374 DLAACIKGLP384 NVQRSDYLNT394 FEFMDKLGEN404 LKIKLAQAKL 414 S
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .AKG or .AKG2 or .AKG3 or :3AKG;style chemicals stick;color identity;select .A:77 or .A:94 or .A:96 or .A:97 or .A:100 or .A:109 or .A:132 or .A:275 or .A:279 or .A:306 or .A:308; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors. Nat Commun. 2022 Aug 15;13(1):4785. | ||||
| REF 2 | Mutant IDH1 enhances the production of 2-hydroxyglutarate due to its kinetic mechanism. Biochemistry. 2013 Jul 2;52(26):4563-77. | ||||
| REF 3 | Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009 Dec 10;462(7274):739-44. | ||||
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